Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Binds hormone or other secreted growth regulatory factor,...
Reexamination Certificate
2001-09-14
2003-12-16
Spector, Lorraine (Department: 1646)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Binds hormone or other secreted growth regulatory factor,...
C424S145100, C424S184100, C514S002600
Reexamination Certificate
active
06663865
ABSTRACT:
The present application is the national stage under 35 U.S.C. 371 of international application PCT/IB00/00052, filed Jan. 19, 2000 which designated the United States, and which international application was published under PCT Article 21(2) in the English language.
FIELD OF THE INVENTION
Tumor necrosis factor antagonists are administered in therapeutically effective doses to treat and/or prevent endometriosis. The antagonists of this invention typically are selected among various classes of molecules but preferably are soluble TNF receptors. The antagonists are useful for the regression of endometriotic lesions and, if combined with other active ingredients, for amelioration of related disorders, like infertility.
BACKGROUND OF THE INVENTION
Endometriosis is a female genital disease characterized by the presence of endometrial glands and stroma outside of the endometrial cavity and uterine musculature. The anatomical sites most often affected are the ovaries, uterosacral ligaments, pelvic peritoneum, rectovaginal septum, cervix, vagina, the fallopian tubes and vulva. Generally endometriosis is likely to infiltrate deeply from the rectovaginal sectum in the underlying tissues and not be visible superficially. Occasionally, foci of endometriosis can be encountered in extraovarian sites, like in lungs, bladder, skin, pleura and lymphnodes. Endometriotic lesions are progressive: they are first seen as clear vescicles, which then become red and then progress to black, fibrotic lesions over a period of few years (MacSween, 1993).
Endometriosis is considered as a benign disease, but endometriotic lesions become occasionally malignant. As in other kind of malignancies, the development of endometriosis-derived neoplasms is due to concurrent events, involving alterations in growth factors and/or oncogenes regulation (Cheung, 1996).
Endometriosis is among the most common gynaecological diseases, with prevalence among reproductive age women: this disease is found in about 5-10% of women in reproductive age (Barbieri, 1988). Endometriotic tisssue is completely dependent on estrogen for continued growth, also in ectopic locations. Consequently, endometriosis is rare before menarche and after menopause, when women are deficient in estrogen. Endometriosis hormonal sensitivity is underlying some of the more common symptoms, which are pelvic pain and dysmenorrhea.
Endometriosis is originated from endometrial cells disseminated from uterus to other locations, where viable cells can implant and grow. Two possible mechanisms have been proposed to explain the initial cell spreading. Retrograde menstruation, a common phenomenon among cycling women, makes possible to endometrium-detached fragments to reach, through menstrual reflux liquid, nearby structures in the genital apparatus. Alternatively, to explain the occurrence of endometriosis in sites other than genital structures, endometrial cells may be spread through uterine veins and extension through the lymphatic system (haematogenous or lymphatic dissemination). Also gynaecological surgery can contribute to this spreading (MacSween, 1993).
Apart from endometrial cells dissemination, other factors, such as genetic predisposition (Malinak et al, 1980), as well as immunological alterations (Ho et al., 1997) may determine women's susceptibility to endometriosis. Since endometrial cells are frequently seen in peritoneal fluid in all women at the time of menses, mammalians should have mechanisms, most probably related to immune system, to avoid the onset of endometriosis In general, endometrial cells that escape the host's immune response and have adequate estrogenic stimulation can proliferate to form large, macroscopically visible lesions. Endometriosis is therefore considered as a dynamic process where new lesions are continuously being formed while existing lesions may grow or be destroyed by the host's immune response.
The inflammatory reaction, normally associated to endometriosis, changes the peritoneal environment, since there is an increased volume of peritoneal fluid and peritoneal macrophages are increased in both number and activity. Therefore, monocyte/macrophage system has been proposed as having a key role in the development of endometriosis. Secretory products of macrophages, including RANTES (Hornung et al., 1997), Interleukin-6 (Harada et al., 1997), Interleukin-8 (Arici et al., 1996a), Tumor Necrosis Factor-alpha (Overton et al., 1996), Monocyte Chemotactic Protein-1 (Arici, et al., 1997), were found at higher concentration in the peritoneal fluid of women affected by this disease. Immunological changes have been demonstrated in women with endometriosis but it has not been demonstrated whether these events are responsible for the endometriosis or are a result of the inflammation caused by endometriosis (Rana et al., 1996).
The knowledge about endometriosis, and its relevance for other disorders, is still now limited, even at diagnostic level. Although endometriosis is considered as a major cause of infertility, studies on the pathophysiology of the disease are contradictory and not definitive. There is a poor correlation between the degree of pain or infertility and the severity of disease, since the early lesions are more metabolically active. The infertility rate is higher than the normal population and studies in rabbits have shown that surgical induction of endometriosis leads to a decrease in fertility from 75% to 25% (Hahn et al., 1986). Patients with pelvic pain were found to have endometriosis 71% of the time, while 84% of patients with pelvic pain and infertility had endometriosis diagnosed (Koninckx, et al., 1991). In general, infertility can be found when endometriosis is so extended to disrupt normal vaginal structure, meanwhile pregnancy rates are normal when endometriosis is minimal.
Endometriosis can affect fertility also in a different way. White blood cell messengers, like Interleukin-6, Interferon and Tumor Necrosis Factor, are all increased, adversely affecting oocyte-sperm interaction. Serum samples obtained from women with endometriosis were found to be embryotoxic in mouse embryo models and to inhibit sperm mobility in vitro (Halme, 1991), an effect enhanced when recombinant Tumor Necrosis Factor-alpha is added (Eisermann, 1989). Those studies, however, did not address the problem on how cytokines affect the progression of endometriosis but only showed the effects of such molecules on the viability of germ and embryonic cells.
Hormonal therapy and surgery are the two therapeutic modalities currently used to treat endometriosis. Current pharmacological therapy for endometriosis requires hormonal suppression of the production of estrogen, so that the poor hormone environment blocks the growth of ectopic tissue. Regarding the treatment of endometriosis-related infertility, hormone therapy in patients with minimal disease is of no proven benefit, meanwhile other studies showed an increase in pregnancy rates (Arici et al., 1996b).
Hormonal therapies have included high dose of progestogens, combinations of estrogen and progesterone (using high dose oral contraceptive pills, or OCPs, in a “pseudopregnancy” regimen), Danazol (an androgenic derivative of ethisterone) and more recently GnRH agonists. These hormonal therapies are effective on pelvic pain and induce an objective regression of lesions, but have several caveats. Estrogen may stimulate and cause proliferation of endometriotic tissue since it may be unable to respond to progesterone, even at high doses so that OCPs may offer partial relief to a limited number of patients (Dawood, 1993). Progestational agents can provoke irregular bleeding (50%) along with depression, weight gain, acid fluid retention. Danazol, suppresses endometriosis evoking various responses, including the reduction of soluble Tumor Necrosis Factor alpha, Interleukin-1 beta and CD8 levels in serum (Matalliotakis, 1997; Mori, 1990), the inhibition of de novo steroidogenesis and displacement of estradiol from its receptor. Danazol can improve symptoms in approximately 66-100% o
Borrelli Francesco
D'Antonio Mauro
Martelli Fabrizio
Applied Research Systems ARS Holding N.V.
Browdy and Neimark PLLC
O'Hara Eileen B.
Spector Lorraine
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